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Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes

Nature Geneticsvolume 50pages559571 (2018) | Download Citation

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Abstract

We aggregated coding variant data for 81,412 type 2 diabetes cases and 370,832 controls of diverse ancestry, identifying 40 coding variant association signals (P < 2.2 × 10−7); of these, 16 map outside known risk-associated loci. We make two important observations. First, only five of these signals are driven by low-frequency variants: even for these, effect sizes are modest (odds ratio ≤1.29). Second, when we used large-scale genome-wide association data to fine-map the associated variants in their regional context, accounting for the global enrichment of complex trait associations in coding sequence, compelling evidence for coding variant causality was obtained for only 16 signals. At 13 others, the associated coding variants clearly represent ‘false leads’ with potential to generate erroneous mechanistic inference. Coding variant associations offer a direct route to biological insight for complex diseases and identification of validated therapeutic targets; however, appropriate mechanistic inference requires careful specification of their causal contribution to disease predisposition.

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Acknowledgements

A full list of acknowledgments appears in the Supplementary Note. Part of this work was conducted using the UK Biobank Resource under application number 9161.

Author information

Author notes

  1. A full list of members and affiliations appears in the Supplementary Note.

  2. These authors jointly directed this work: Danish Saleheen, Andrew P. Morris, Jerome I. Rotter and Mark I. McCarthy

Affiliations

  1. Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK

    • Anubha Mahajan
    • , Neil R. Robertson
    • , Wei Gan
    • , Hidetoshi Kitajima
    • , N. William Rayner
    • , Juan Fernandez Tajes
    • , Cecilia M. Lindgren
    • , Jonathan Marchini
    • , Andrew P. Morris
    •  & Mark I. McCarthy
  2. Departments of Epidemiology and Medicine, Diabetes Translational Research Center, Indiana University, Indianapolis, IN, USA

    • Jennifer Wessel
  3. MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK

    • Sara M. Willems
    • , Claudia Langenberg
    • , Nicholas J. Wareham
    •  & Robert A. Scott
  4. Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, PA, USA

    • Wei Zhao
    • , Jung-Jin Lee
    •  & Danish Saleheen
  5. Oxford Centre for Diabetes, Endocrinology, and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK

    • Neil R. Robertson
    • , N. William Rayner
    • , Matt Neville
    • , Katharine R. Owen
    • , Fredrik Karpe
    •  & Mark I. McCarthy
  6. National Heart, Lung, and Blood Institute’s Framingham Heart Study, Framingham, MA, USA

    • Audrey Y. Chu
    •  & Josée Dupuis
  7. Division of Preventive Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston, MA, USA

    • Audrey Y. Chu
    • , Paul M. Ridker
    •  & Daniel I. Chasman
  8. Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA

    • Daniel Taliun
    • , Vassily Vladimirovich Trubetskoy
    • , Tanya M. Teslovich
    • , Pranav Yajnik
    •  & Michael Boehnke
  9. Department of Human Genetics, Wellcome Trust Sanger Institute, Hinxton, UK

    • N. William Rayner
    • , Bram Peter Prins
    • , Sophie Hackinger
    • , Nicole Soranzo
    • , Eleftheria Zeggini
    •  & Inês Barroso
  10. Department of Pediatrics, The Institute for Translational Genomics and Population Sciences, LABioMed at Harbor-UCLA Medical Center, Torrance, CA, USA

    • Xiuqing Guo
    • , Yii-Der Ida Chen
    • , Yang Hai
    • , Kent D. Taylor
    • , Jie Yao
    •  & Jerome I. Rotter
  11. Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    • Yingchang Lu
    • , Michael Preuss
    • , Erwin P. Bottinger
    •  & Ruth J. F. Loos
  12. Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA

    • Man Li
    •  & Elizabeth Selvin
  13. Division of Nephrology and Hypertension, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT, USA

    • Man Li
  14. Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Services, University of Washington, Seattle, WA, USA

    • Richard A. Jensen
    • , Jennifer A. Brody
    • , Susan R. Heckbert
    •  & Bruce M. Psaty
  15. Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of the Chinese Academy of Sciences, Shanghai, People’s Republic of China

    • Yao Hu
    • , Shaofeng Huo
    • , Huaixing Li
    •  & Xu Lin
  16. Department of Biostatistical Sciences, Division of Public Health Sciences, Wake Forest University Health Sciences, Winston-Salem, NC, USA

    • Kurt K. Lohman
  17. Department of Epidemiology and Biostatistics, Imperial College London, London, UK

    • Weihua Zhang
    • , Saima Afaq
    • , Benjamin Lehne
    • , Marie Loh
    •  & John Campbell Chambers
  18. Department of Cardiology, Ealing Hospital, London North West Healthcare NHS Trust, Middlesex, UK

    • Weihua Zhang
    • , John Campbell Chambers
    •  & Jaspal Singh Kooner
  19. Department of Biostatistics, University of Liverpool, Liverpool, UK

    • James P. Cook
    •  & Andrew P. Morris
  20. Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA

    • Jason Flannick
    • , Gina Marie Peloso
    • , Noël P. Burtt
    • , Sekar Kathiresan
    •  & Cecilia M. Lindgren
  21. Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA

    • Jason Flannick
  22. Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

    • Niels Grarup
    • , Jette Bork-Jensen
    • , Torben Hansen
    •  & Oluf Pedersen
  23. Department of Clinical Sciences, Diabetes, and Endocrinology, Lund University Diabetes Centre, Malmö, Sweden

    • Jasmina Kravic
    • , Emma Ahlqvist
    • , Anders H. Rosengren
    •  & Leif Groop
  24. Center for Genome Science, Korea National Institute of Health, Chungcheongbuk-do, Republic of Korea

    • Young Jin Kim
    • , Sohee Han
    • , Bong-Jo Kim
    • , Sung Soo Kim
    •  & Bok-Ghee Han
  25. Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA

    • Denis V. Rybin
    • , Gina Marie Peloso
    • , Ching-Ti Liu
    •  & Josée Dupuis
  26. Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, UK

    • Hanieh Yaghootkar
    • , Andrew R. Wood
    •  & Timothy M. Frayling
  27. Institute of Genetic Epidemiology, Helmholtz Zentrum München–German Research Center for Environmental Health, Neuherberg, Germany

    • Martina Müller-Nurasyid
    •  & Konstantin Strauch
  28. Department of Medicine I, University Hospital Großhadern, Ludwig-Maximilians-Universität, Munich, Germany

    • Martina Müller-Nurasyid
  29. DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany

    • Martina Müller-Nurasyid
    •  & Annette Peters
  30. Department of Molecular Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), Nuthetal, Germany

    • Karina Meidtner
    • , Susanne Jäger
    •  & Matthias B. Schulze
  31. German Center for Diabetes Research (DZD), Neuherberg, Germany

    • Karina Meidtner
    • , Susanne Jäger
    • , Jennifer Kriebel
    • , Wolfgang Rathmann
    • , Barbara Thorand
    • , Annette Peters
    • , Harald Grallert
    •  & Matthias B. Schulze
  32. Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands

    • Ruifang Li-Gao
    • , Hugoline G. de Haan
    • , Renée de Mutsert
    • , Frits R. Rosendaal
    •  & Dennis Mook-Kanamori
  33. Department of Clinical Sciences, Lund University Diabetes Centre, Genetic and Molecular Epidemiology Unit, Lund University, Malmö, Sweden

    • Tibor V. Varga
    •  & Paul W. Franks
  34. MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK

    • Jonathan Marten
    •  & Caroline Hayward
  35. Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA

    • Jin Li
    •  & Erik Ingelsson
  36. Icelandic Heart Association, Kopavogur, Iceland

    • Albert Vernon Smith
    •  & Vilmundur Gudnason
  37. Faculty of Medicine, University of Iceland, Reykjavik, Iceland

    • Albert Vernon Smith
    • , Vilmundur Gudnason
    • , Kari Stefansson
    •  & Unnur Thorsteinsdottir
  38. Department of Genetics, Division of Statistical Genomics, Washington University School of Medicine, St. Louis, MO, USA

    • Ping An
    •  & Michael A. Province
  39. Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands

    • Symen Ligthart
    • , Ayse Demirkan
    • , Najaf Amin
    • , Jun Liu
    • , Abbas Dehghan
    • , Fernando Rivadineira
    • , Cornelia van Duijn
    •  & Oscar H. Franco
  40. Department of Medical Sciences, Molecular Epidemiology, and Science for Life Laboratory, Uppsala University, Uppsala, Sweden

    • Stefan Gustafsson
    • , André G. Uitterlinden
    •  & Erik Ingelsson
  41. Section of Biology and Genetics, Department of Neurosciences, Biomedicine, and Movement Sciences, University of Verona, Verona, Italy

    • Giovanni Malerba
    •  & Cristina Bombieri
  42. Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands

    • Ayse Demirkan
  43. deCODE Genetics/Amgen, Inc., Reykjavik, Iceland

    • Valgerdur Steinthorsdottir
    • , Gudmar Thorleifsson
    • , Kari Stefansson
    •  & Unnur Thorsteinsdottir
  44. Institute of Genetic Epidemiology, Medical Center–University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany

    • Matthias Wuttke
    •  & Anna Köttgen
  45. CNRS, UMR 8199, Lille University, Lille Pasteur Institute, Lille, France

    • Cécile Lecoeur
    • , Mickaël Canouil
    • , Loïc Yengo
    •  & Philippe Froguel
  46. Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA

    • Lawrence F. Bielak
    • , Patricia A. Peyser
    •  & Sharon L. R. Kardia
  47. Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA

    • Marielisa Graff
    •  & Anne E. Justice
  48. Human Genetics Center, University of Texas Graduate School of Biomedical Sciences at Houston, University of Texas Health Science Center at Houston, Houston, TX, USA

    • Heather M. Highland
  49. Department of Public Health Sciences, Institute of Personalized Medicine, Penn State College of Medicine, Hershey, PA, USA

    • Dajiang J. Liu
  50. William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK

    • Eirini Marouli
    • , Helen R. Warren
    • , Ioanna Ntalla
    •  & Panos Deloukas
  51. National Institute for Health Research, Barts Cardiovascular Biomedical Research Unit, Queen Mary University of London, London, UK

    • Helen R. Warren
  52. Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark

    • Shoaib Afzal
    • , Sune F. Nielsen
    • , Line Rode
    • , Anette Varbo
    •  & Børge G. Nordestgaard
  53. Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark

    • Shoaib Afzal
    • , Anne Tybjærg-Hansen
    • , Sune F. Nielsen
    • , Line Rode
    • , Anette Varbo
    •  & Børge G. Nordestgaard
  54. Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

    • Shoaib Afzal
    • , Anne Tybjærg-Hansen
    • , Torben Jørgensen
    • , Sune F. Nielsen
    • , Anette Varbo
    •  & Børge G. Nordestgaard
  55. Department of Clinical Sciences, Hypertension, and Cardiovascular Disease, Lund University, Malmö, Sweden

    • Peter Almgren
    •  & Olle Melander
  56. Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark

    • Lia B. Bang
  57. Department of Epidemiology and Prevention, Public Health Sciences, Wake Forest University Health Sciences, Winston-Salem, NC, USA

    • Alain G. Bertoni
    •  & Yongmei Liu
  58. Institute of Regional Health Research, University of Southern Denmark, Odense, Denmark

    • Ivan Brandslund
  59. Department of Clinical Biochemistry, Vejle Hospital, Vejle, Denmark

    • Ivan Brandslund
  60. Department of Biomedical Science, Hallym University, Chuncheon, Republic of Korea

    • Yoon Shin Cho
  61. Medical Department, Lillebælt Hospital Vejle, Vejle, Denmark

    • Cramer Christensen
  62. Institute of Cardiovascular Science, University College London, London, UK

    • Sophie V. Eastwood
  63. Department of Nephrology and Medical Intensive Care, Charité, University Medicine Berlin, Berlin, Germany

    • Kai-Uwe Eckardt
  64. Estonian Genome Center, University of Tartu, Tartu, Estonia

    • Krista Fischer
    • , Kristi Läll
    • , Reedik Mägi
    • , Andres Metspalu
    •  & Andrew P. Morris
  65. Institute of Internal and Geriatric Medicine, Università Cattolica del Sacro Cuore, Rome, Italy

    • Giovanni Gambaro
  66. Department of Public Health and Caring Sciences, Geriatrics, Uppsala University, Uppsala, Sweden

    • Vilmantas Giedraitis
    •  & Martin Ingelsson
  67. Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX, USA

    • Megan L. Grove
    •  & Eric Boerwinkle
  68. Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark

    • Anne Tybjærg-Hansen
    •  & Anette Varbo
  69. Diabetes Research Center (Diabetes Unit), Department of Medicine, Massachusetts General Hospital, Boston, MA, USA

    • Marie-France Hivert
    •  & Jose C. Florez
  70. Department of Population Medicine, Harvard Pilgrim Health Care Institute, Harvard Medical School, Boston, MA, USA

    • Marie-France Hivert
  71. Department of Medicine, Université de Sherbrooke, Sherbrooke, Quebec, Canada

    • Marie-France Hivert
  72. Malmska Municipal Health Care Center and Hospital, Jakobstad, Finland

    • Bo Isomaa
  73. Folkhälsan Research Centre, Helsinki, Finland

    • Bo Isomaa
    •  & Tiinamaija Tuomi
  74. Steno Diabetes Center Copenhagen, Gentofte, Denmark

    • Marit E. Jørgensen
  75. National Institute of Public Health, Southern Denmark University, Copenhagen, Denmark

    • Marit E. Jørgensen
  76. Research Centre for Prevention and Health, Capital Region of Denmark, Glostrup, Denmark

    • Torben Jørgensen
    •  & Allan Linneberg
  77. Faculty of Medicine, Aalborg University, Aalborg, Denmark

    • Torben Jørgensen
  78. Department of Primary Health Care, Vaasa Central Hospital, Vaasa, Finland

    • Annemari Käräjämäki
  79. Diabetes Center, Vaasa Health Care Center, Vaasa, Finland

    • Annemari Käräjämäki
  80. Department of Health, National Institute for Health and Welfare, Helsinki, Finland

    • Heikki A. Koistinen
    •  & Jaakko Tuomilehto
  81. Endocrinology, Abdominal Center, Helsinki University Hospital, Helsinki, Finland

    • Heikki A. Koistinen
    •  & Tiinamaija Tuomi
  82. Minerva Foundation Institute for Medical Research, Helsinki, Finland

    • Heikki A. Koistinen
  83. Department of Medicine, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland

    • Heikki A. Koistinen
  84. Integrated Research and Treatment (IFB) Center Adiposity Diseases, University of Leipzig, Leipzig, Germany

    • Peter Kovacs
    •  & Matthias Blüher
  85. Research Unit of Molecular Epidemiology, Institute of Epidemiology II, Helmholtz Zentrum München–German Research Center for Environmental Health, Neuherberg, Germany

    • Jennifer Kriebel
    •  & Harald Grallert
  86. Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Innsbruck, Austria

    • Florian Kronenberg
    •  & Sebastian Schönherr
  87. Institute of Mathematical Statistics, University of Tartu, Tartu, Estonia

    • Kristi Läll
  88. Department of Medicine, Division of Bioinformatics and Personalized Medicine, University of Colorado Denver, Aurora, CO, USA

    • Leslie A. Lange
  89. Department of Ophthalmology, Taichung Veterans General Hospital, Taichung, Taiwan

    • Keng-Hung Lin
  90. Department of Clinical Experimental Research, Rigshospitalet, Glostrup, Denmark

    • Allan Linneberg
  91. Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

    • Allan Linneberg
  92. Institute of Health Sciences, University of Oulu, Oulu, Finland

    • Marie Loh
  93. Translational Laboratory in Genetic Medicine (TLGM), Agency for Science, Technology, and Research (A*STAR), Singapore, Singapore

    • Marie Loh
  94. Dromokaiteio Psychiatric Hospital, National and Kapodistrian University of Athens, Athens, Greece

    • Vasiliki Mamakou
  95. Department of Preventive Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA

    • Roberta McKean-Cowdin
  96. Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    • Girish Nadkarni
  97. Oxford NIHR Biomedical Research Centre, Oxford University Hospitals Trust, Oxford, UK

    • Matt Neville
    • , Katharine R. Owen
    • , Fredrik Karpe
    •  & Mark I. McCarthy
  98. Institute for Biometrics and Epidemiology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany

    • Wolfgang Rathmann
  99. Department of Biostatistics, University of Washington, Seattle, WA, USA

    • Kenneth Rice
  100. Center for Public Health Genomics, Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, USA

    • Stephen S. Rich
  101. Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden

    • Olov Rolandsson
    •  & Paul W. Franks
  102. Department of Twins Research and Genetic Epidemiology, King’s College London, London, UK

    • Kerrin S. Small
    •  & Timothy D. Spector
  103. Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland

    • Alena Stančáková
    • , Johanna Kuusisto
    •  & Markku Laakso
  104. MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK

    • Praveen Surendran
    • , Robin Young
    • , Adam S. Butterworth
    •  & John Danesh
  105. Institute of Epidemiology II, Helmholtz Zentrum München–German Research Center for Environmental Health, Neuherberg, Germany

    • Barbara Thorand
    •  & Annette Peters
  106. Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA

    • Adrienne Tin
  107. Department of Medicine, University of Leipzig, Leipzig, Germany

    • Anke Tönjes
    •  & Matthias Blüher
  108. Department of Public Health, Aarhus University, Aarhus, Denmark

    • Daniel R. Witte
  109. Danish Diabetes Academy, Odense, Denmark

    • Daniel R. Witte
  110. Robertson Centre for Biostatistics, University of Glasgow, Glasgow, UK

    • Robin Young
  111. Institut Pasteur de Lille, INSERM U1167, Université Lille Nord de France, Lille, France

    • Philippe Amouyel
  112. Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), Nuthetal, Germany

    • Heiner Boeing
  113. Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA

    • Eric Boerwinkle
  114. Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK

    • Rajiv Chowdhury
    •  & Joanna M. M. Howson
  115. Genome Technology Branch, National Human Genome Research Institute, US National Institutes of Health, Bethesda, MD, USA

    • Francis S. Collins
  116. Department of Nutrition and Dietetics, Harokopio University of Athens, Athens, Greece

    • George Dedoussis
  117. MRC–PHE Centre for Environment and Health, Imperial College London, London, UK

    • Abbas Dehghan
  118. Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, Jeddah, Saudi Arabia

    • Panos Deloukas
  119. Research Centre on Epidemiology and Preventive Medicine (EPIMED), Department of Medicine and Surgery, University of Insubria, Varese, Italy

    • Marco M. Ferrario
  120. INSERM, UMR 1027, Toulouse, France

    • Jean Ferrières
  121. Department of Cardiology, Toulouse University School of Medicine, Rangueil Hospital, Toulouse, France

    • Jean Ferrières
  122. Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA

    • Jose C. Florez
    •  & Sekar Kathiresan
  123. Programs in Metabolism and Medical & Population Genetics, Broad Institute, Cambridge, MA, USA

    • Jose C. Florez
  124. Department of Medicine, Harvard Medical School, Boston, MA, USA

    • Jose C. Florez
    • , Sekar Kathiresan
    • , Paul M. Ridker
    •  & Daniel I. Chasman
  125. Center for Non-Communicable Diseases, Karachi, Pakistan

    • Philippe Frossard
    • , Asif Rasheed
    •  & Danish Saleheen
  126. Laboratory of Epidemiology and Population Sciences, National Institute on Aging, US National Institutes of Health, Bethesda, MD, USA

    • Tamara B. Harris
    •  & Lenore J. Launer
  127. Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA

    • Sekar Kathiresan
  128. UKCRC Centre of Excellence for Public Health (NI), Queens University of Belfast, Belfast, UK

    • Frank Kee
  129. Big Data Institute, Li Ka Shing Centre For Health Information and Discovery, University of Oxford, Oxford, UK

    • Cecilia M. Lindgren
  130. National Institute for Health and Welfare, Helsinki, Finland

    • Satu Männistö
    • , Markus Perola
    •  & Veikko Salomaa
  131. Institute of Human Genetics, Technische Universität München, Munich, Germany

    • Thomas Meitinger
    •  & Kari Kuulasmaa
  132. Institute of Human Genetics, Helmholtz Zentrum München–German Research Center for Environmental Health, Neuherberg, Germany

    • Thomas Meitinger
  133. Department of Genetics, University of North Carolina, Chapel Hill, NC, USA

    • Karen L. Mohlke
  134. Department of Epidemiology and Public Health, University of Strasbourg, Strasbourg, France

    • Marie Moitry
  135. Department of Public Health, University Hospital of Strasbourg, Strasbourg, France

    • Marie Moitry
  136. Clinical Research Centre, Centre for Molecular Medicine, Ninewells Hospital and Medical School, Dundee, UK

    • Andrew D. Morris
  137. Usher Institute to the Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK

    • Andrew D. Morris
  138. Aberdeen Biomedical Imaging Centre, School of Medicine, Medical Sciences, and Nutrition, University of Aberdeen, Aberdeen, UK

    • Alison D. Murray
  139. Department of Clinical Sciences, Diabetes, and Cardiovascular Disease, Genetic Epidemiology, Lund University, Malmö, Sweden

    • Marju Orho-Melander
  140. Finnish Institute for Molecular Medicine (FIMM), University of Helsinki, Helsinki, Finland

    • Markus Perola
    • , Leif Groop
    •  & Tiinamaija Tuomi
  141. Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands

    • Fernando Rivadineira
    •  & André G. Uitterlinden
  142. Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan

    • Wayne H.-H. Sheu
  143. National Yang-Ming University, School of Medicine, Taipei, Taiwan

    • Wayne H.-H. Sheu
  144. National Defense Medical Center, School of Medicine, Taipei, Taiwan

    • Wayne H.-H. Sheu
  145. McGill University and Génome Québec Innovation Centre, Montreal, QC, Canada

    • Rob Sladek
  146. Department of Human Genetics, McGill University, Montreal, QC, Canada

    • Rob Sladek
  147. Division of Endocrinology and Metabolism, Department of Medicine, McGill University, Montreal, QC, Canada

    • Rob Sladek
  148. Division of Population Health Sciences, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK

    • Blair H. Smith
  149. Institute of Medical Informatics, Biometry, and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany

    • Konstantin Strauch
  150. USC Roski Eye Institute, Department of Ophthalmology, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA

    • Rohit Varma
  151. Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI, USA

    • Cristen J. Willer
  152. Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA

    • Cristen J. Willer
  153. Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA

    • Cristen J. Willer
  154. NIHR Blood and Transplant Research Unit in Donor Health and Genomics, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK

    • Adam S. Butterworth
    • , John Danesh
    •  & Nicole Soranzo
  155. Imperial College Healthcare NHS Trust, Imperial College London, London, UK

    • John Campbell Chambers
    •  & Jaspal Singh Kooner
  156. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK

    • John Danesh
  157. British Heart Foundation, Cambridge Centre of Excellence, Department of Medicine, University of Cambridge, Cambridge, UK

    • John Danesh
  158. Department of Nutrition, Harvard School of Public Health, Boston, MA, USA

    • Paul W. Franks
  159. Department of Genomics of Common Disease, School of Public Health, Imperial College London, London, UK

    • Philippe Froguel
  160. Clinical Cooperation Group Type 2 Diabetes, Helmholtz Zentrum München, Ludwig-Maximillians University Munich, Munich, Germany

    • Harald Grallert
  161. Clinical Cooperation Group Nutrigenomics and Type 2 Diabetes, Helmholtz Zentrum München, Technical University of Munich, Munich, Germany

    • Harald Grallert
  162. Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark

    • Torben Hansen
  163. University of Exeter Medical School, University of Exeter, Exeter, UK

    • Andrew T. Hattersley
  164. National Heart and Lung Institute, Cardiovascular Sciences, Hammersmith Campus, Imperial College London, London, UK

    • Jaspal Singh Kooner
  165. Department of Medical Sciences, Uppsala University, Uppsala, Sweden

    • Lars Lind
  166. Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    • Ruth J. F. Loos
  167. Department of Statistics, University of Oxford, Oxford, UK

    • Jonathan Marchini
  168. Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, The Netherlands

    • Dennis Mook-Kanamori
  169. Pat Macpherson Centre for Pharmacogenetics and Pharmacogenomics, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK

    • Colin N. A. Palmer
  170. Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN, USA

    • James S. Pankow
  171. Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA

    • Bruce M. Psaty
  172. Foundation for Research in Health, Exercise, and Nutrition, Kuopio Research Institute of Exercise Medicine, Kuopio, Finland

    • Rainer Rauramaa
  173. Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK

    • Naveed Sattar
  174. Department of Hematology, School of Clinical Medicine, University of Cambridge, Cambridge, UK

    • Nicole Soranzo
  175. Divisions of Endocrinology and Nephrology, University Hospital Leipzig, Leipzig, Germany

    • Michael Stumvoll
  176. Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland

    • Tiinamaija Tuomi
  177. Dasman Diabetes Institute, Dasman, Kuwait

    • Jaakko Tuomilehto
  178. Department of Neuroscience and Preventive Medicine, Danube University Krems, Krems, Austria

    • Jaakko Tuomilehto
  179. Diabetes Research Group, King Abdulaziz University, Jeddah, Saudi Arabia

    • Jaakko Tuomilehto
  180. Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA

    • James G. Wilson
  181. Metabolic Research Laboratories, Wellcome Trust–MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK

    • Inês Barroso
  182. Division of Endocrinology, Diabetes, and Metabolism, Cedars-Sinai Medical Center, Los Angeles, CA, USA

    • Mark O. Goodarzi
  183. General Medicine Division, Massachusetts General Hospital and Department of Medicine, Harvard Medical School, Boston, MA, USA

    • James B. Meigs
  184. Department of Medicine, Institute for Translational Genomics and Population Sciences, LABioMed at Harbor-UCLA Medical Center, Torrance, CA, USA

    • Jerome I. Rotter

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Consortia

  1. ExomeBP Consortium

    1. MAGIC Consortium

      1. GIANT Consortium

        Contributions

        Project coordination: A. Mahajan, A.P.M., J.I.R., M.I.M. Core analyses and writing: A. Mahajan, J.W., S.M.W., W. Zhao, N.R.R., A.Y.C., W.G., H.K., R.A.S., I. Barroso, T.M.F., M.O.G., J.B.M., M. Boehnke, D.S., A.P.M., J.I.R., M.I.M. Statistical analysis in individual studies: A. Mahajan, J.W., S.M.W., W. Zhao, N.R.R., A.Y.C., W.G., H.K., D.T., N.W.R., X.G., Y. Lu, M. Li, R.A.J., Y. Hu, S. Huo, K.K.L., W. Zhang, J.P.C., B.P.P., J. Flannick, N.G., V.V.T., J. Kravic, Y.J.K., D.V.R., H.Y., M.M.-N., K.M., R.L.-G., T.V.V., J. Marten, J. Li, A.V.S., P. An, S.L., S.G., G.M., A. Demirkan, J.F.T., V. Steinthorsdottir, M.W., C. Lecoeur, M. Preuss, L.F.B., P. Almgren, J.B.-J., J.A.B., M.C., K.-U.E., K.F.,H.G.d.H., Y. Hai, S. Han, S.J., F. Kronenberg, K.L., L.A.L., J.-J.L., H.L., C.-T.L., J. Liu, R.M., K.R., S.S., P.S., T.M.T., G.T., A. Tin, A.R.W., P.Y., J.Y., L.Y., R.Y., J.C.C., D.I.C., C.v.D., J. Dupuis, P.W.F., A. Köttgen, D.M.-K., N. Soranzo, R.A.S., A.P.M. Genotyping: A. Mahajan, N.R.R., A.Y.C., Y. Lu, Y. Hu, S. Huo, B.P.P., N.G., R.L.-G., P. An, G.M., E.A., N.A., C.B., N.P.B., Y.-D.I.C., Y.S.C., M.L.G., H.G.d.H., S. Hackinger, S.J., B.-J.K., P.K., J. Kriebel, F. Kronenberg, H.L., S.S.R., K.D.T., E.B., E.P.B., P.D., J.C.F., S.R.H., C. Langenberg, M.A.P., F.R., A.G.U., J.C.C., D.I.C., P.W.F., B.-G.H., C.H., E.I., S.L.R.K., J.S.K., Y. Liu, R.J.F.L., N. Soranzo, N.J.W., R.A.S., T.M.F., A.P.M., J.I.R., M.I.M. Cross-trait lookups in unpublished data: S.M.W., A.Y.C., Y. Lu, M. Li, M.G., H.M.H., A.E.J., D.J.L., E.M., G.M.P., H.R.W., S.K., C.J.W. Phenotyping: Y. Lu, Y. Hu, S. Huo, P. An, S.L., A. Demirkan, S. Afaq, S. Afzal, L.B.B., A.G.B., I. Brandslund, C.C., S.V.E., G.G., V. Giedraitis, A.T.-H., M.-F.H., B.I., M.E.J., T.J., A. Käräjämäki, S.S.K., H.A.K., P.K., F. Kronenberg, B.L., H.L., K.-H.L., A.L., J. Liu, M. Loh, V.M., R.M.-C., G.N., M.N., S.F.N., I.N., P.A.P., W.R., L.R., O.R., S.S., E.S., K.S.S., A.S., B.T., A. Tönjes, A.V., D.R.W., H.B., E.P.B., A. Dehghan, J.C.F., S.R.H., C. Langenberg, A.D. Morris, R.d.M., M.A.P., A.R., P.M.R., F.R.R., V. Salomaa, W.H.-H.S., R.V., J.C.C., J. Dupuis, O.H.F., H.G., B.-G.H., T.H., A.T.H., C.H., S.L.R.K., J.S.K., A. Köttgen, L.L., Y. Liu, R.J.F.L., C.N.A.P., J.S.P., O.P., B.M.P., M.B.S., N.J.W., T.M.F., M.O.G. Individual study design and principal investigators: N.G., P. An, B.-J.K., P. Amouyel, H.B., E.B., E.P.B., R.C., F.S.C., G.D., A. Dehghan, P.D., M.M.F., J. Ferrières, J.C.F., P. Frossard, V. Gudnason, T.B.H., S.R.H., J.M.M.H., M.I., F. Kee, J. Kuusisto, C. Langenberg, L.J.L., C.M.L., S.M., T.M., O.M., K.L.M., M.M., A.D. Morris, A.D. Murray, R.d.M., M.O.-M., K.R.O., M. Perola, A.P., M.A.P., P.M.R., F.R., F.R.R., A.H.R., V. Salomaa, W.H.-H.S., R.S., B.H.S., K. Strauch, A.G.U., R.V., M. Blüher, A.S.B., J.C.C., D.I.C., J. Danesh, C.v.D., O.H.F., P.W.F., P. Froguel, H.G., L.G., T.H., A.T.H., C.H., E.I., S.L.R.K., F. Karpe, J.S.K., A. Köttgen, K.K., M. Laakso, X.L., L.L., Y. Liu, R.J.F.L., J. Marchini, A. Metspalu, D.M.-K., B.G.N., C.N.A.P., J.S.P., O.P., B.M.P., R.R., N. Sattar, M.B.S., N. Soranzo, T.D.S., K. Stefansson, M.S., U.T., T.T., J.T., N.J.W., J.G.W., E.Z., I. Barroso, T.M.F., J.B.M., M. Boehnke, D.S., A.P.M., J.I.R., M.I.M.

        Competing interests

        J.C.F. has received consulting honoraria from Merck and from Boehringer-Ingelheim. D.I.C. received funding for exome chip genotyping in the WGHS from Amgen. O.H.F. works in ErasmusAGE, a center for aging research across the life course funded by Nestlé Nutrition (Nestec, Ltd.), Metagenics, Inc., and AXA. Nestlé Nutrition (Nestec, Ltd.), Metagenics, Inc., and AXA had no role in the design or conduct of the study; collection, management, analysis, or interpretation of the data; or preparation, review, or approval of the manuscript. E.I. is an advisor and consultant for Precision Wellness, Inc., and an advisor for Cellink for work unrelated to the present project. B.M.P. serves on the DSMB for a clinical trial funded by the manufacturer (Zoll LifeCor) and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. I. Barroso and spouse own stock in GlaxoSmithKline and Incyte Corporation. T.F. has consulted for Boeringer–Ingelheim and Sanofi on the genetics of diabetes. D.S. has received support from Pfizer, Regeneron, Genentech, and Eli Lilly. M.I.M. has served on advisory panels for Novo Nordisk and Pfizer and received honoraria from Novo Nordisk, Pfizer, Sanofi-Aventis, and Eli Lilly.

        Corresponding authors

        Correspondence to Anubha Mahajan or Jerome I. Rotter or Mark I. McCarthy.

        Supplementary information

        1. Supplementary Text and Figures

          Supplementary Figures 1–7, Supplementary Tables 3–8 and Supplementary Note

        2. Life Sciences Reporting Summary

        3. Supplementary Tables

          Supplementary Tables 1, 2 and 9–11

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        DOI

        https://doi.org/10.1038/s41588-018-0084-1